Serotonin neuron development: shaping molecular and structural identities

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Abstract

<p class="first" id="P1">The continuing fascination with serotonin (5-HT) as a nervous system chemical messenger began with its discovery in the brains of mammals in 1953. Among the many reasons for this decades-long interest is that the small numbers of neurons that make 5-HT influence the excitability of neural circuits in nearly every region of the brain and spinal cord. A further reason is that 5-HT dysfunction has been linked to a range of psychiatric and neurological disorders many of which have a neurodevelopmental component. This has led to intense interest in understanding 5-HT neuron development with the aim of determining whether early alterations in their generation lead to brain disease susceptibility. Here, we present an overview of the neuroanatomical organization of vertebrate 5-HT neurons, their neurogenesis, and prodigious axonal architectures, which enables the expansive reach of 5-HT neuromodulation in the CNS. We review recent findings that have revealed the molecular basis for the tremendous diversity of 5-HT neuron subtypes, the impact of environmental factors on 5-HT neuron development, and how 5-HT axons are topographically organized through disparate signaling pathways. We summarize studies of the gene regulatory networks that control the differentiation, maturation and maintenance of 5-HT neurons. These studies show that the regulatory factors controlling acquisition of 5-HT-type transmitter identity continue to play critical roles in the functional maturation and the maintenance of 5-HT neurons. New insights are presented into how continuously expressed 5-HT regulatory factors control 5-HT neurons at different stages of life and how the regulatory networks themselves are maintained. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/b9e5f63f-0b08-444c-8a85-fab8af4a1f1e/PubMedCentral/image/nihms905898u1.jpg"/> </div> </p>

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The developmental role of serotonin: news from mouse molecular genetics.

Patrícia Lopes Gaspar, Olivier Cases, Luc Maroteaux (2004)

New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.

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Several lines of investigation have helped clarify the role of GAP-43 (FI, B-50 or neuromodulin) in regulating the growth state of axon terminals. In transgenic mice, overexpression of GAP-43 leads to the spontaneous formation of new synapses and enhanced sprouting after injury. Null mutation of the GAP-43 gene disrupts axonal pathfinding and is generally lethal shortly after birth. Manipulations of GAP-43 expression likewise have profound effects on neurite outgrowth for cells in culture. GAP-43 appears to be involved in transducing intra- and extracellular signals to regulate cytoskeletal organization in the nerve ending. Phosphorylation by protein kinase C is particularly significant in this regard, and is linked with both nerve-terminal sprouting and long-term potentiation. In the brains of humans and other primates, high levels of GAP-43 persist in neocortical association areas and in the limbic system throughout life, where the protein might play an important role in mediating experience-dependent plasticity.

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The diverse array of behavioral effects of serotonin form the basis for understanding its potential role as an etiological marker in psychiatric disorders and for the successful pharmacologic intervention of drugs regulating serotonin neurotransmission in behavior. General theories of the behavioral functions of serotonin have implicated serotonin as a general inhibitor of behavioral responding and in modulating motor behavior. The ability of serotonin to regulate behavioral satiety and macronutrient selection provides the basis for pharmacologic treatment of obesity and eating disorders. The role of serotonin in behavioral suppression may be important in social behavior involving aggression and anxiety. The role of serotonin in neuroendocrine regulation provides a basis for understanding serotonin dysregulation in depression. Animal behavior tests are being used to better understand the neural substrates underlying the behavioral effects of antidepressant drugs and to address important issues in clinical treatment. The integration of information between basic and clinical studies provides the basis for future development of more sophisticated pharmacologic treatments of psychiatric disorders.